US8039018B2ExpiredUtilityPatentIndex 81
Solid dosage form of wetted heparin
Est. expiryMay 6, 2024(expired)· nominal 20-yr term from priority
A61K 9/1617A61P 7/02A61K 9/1623A61K 31/727A61K 9/1641A61K 9/4866A61K 31/609
81
PatentIndex Score
18
Cited by
100
References
105
Claims
Abstract
The present invention relates to a solid pharmaceutical composition (such as a solid dosage form) comprising a delivery agent and wetted heparin. The inclusion of wetted heparin rather than un-wetted heparin in the solid pharmaceutical composition results in increased delivery of the heparin. Without being bound by any particular theory, applicants believe that because the polymer chain of the wetted heparin is already in an “open” form, while un-wetted heparin is not, less of the wetted heparin is broken down in the gastrointestinal tract and is more readily absorbed in the stomach.
Claims
exact text as granted — not AI-modified1. A solid pharmaceutical composition comprising:
(a) a delivery agent; and
(b) wetted heparin,
wherein the delivery agent is of the formula:
wherein
R 1 , R 2 , R 3 and R 4 are independently hydrogen, —OH, —NR 6 R 7 , halogen C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
R 5 is a substituted or unsubstituted C 2 -C 16 alkylene, or substituted or unsubstituted C 2 -C 16 alkenylene; and
R 6 and R 7 are independently hydrogen, oxygen or C 1 -C 4 alkyl.
2. The solid pharmaceutical composition of claim 1 , wherein the delivery agent is selected from N-(8-[2-hydroxybenzoyl]-amino)caprylic acid, N-(10-[2-hydroxybenzoyl] amino)decanoic acid, 8-(N-2-hydroxy-5-chlorobenzoyl)aminocaprylic acid, 8-(N-2-Hydroxy-4-methoxybenzoyl)aminocaprylic acid, 4-[(4-chloro, 2-hydroxybenzoyl) -amino]butanoic acid, pharmaceutically acceptable salts thereof, and mixtures thereof.
3. The solid pharmaceutical composition of claim 2 , wherein the delivery agent is N-[8-(2-hydroxybenzoyl)amino]caprylic acid or a pharmaceutically acceptable salt thereof.
4. The solid pharmaceutical composition of claim 3 , wherein the delivery agent is monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate.
5. The solid pharmaceutical composition of claim 3 , wherein the delivery agent is N-(10-[2-hydroxybenzoyl]amino)decanoic acid, or a pharmaceutically acceptable salt thereof.
6. The solid pharmaceutical composition of claim 1 , wherein the heparin in the wetted heparin is selected from unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, and mixtures thereof.
7. The solid pharmaceutical composition of claim 1 , wherein the heparin in the wetted heparin is unfractionated heparin.
8. The solid pharmaceutical composition of claim 1 , wherein the heparin in the wetted heparin is low molecular weight heparin.
9. The solid dosage form of claim 1 , wherein the heparin in the wetted heparin is very low molecular weight heparin.
10. The solid pharmaceutical composition of claim 1 , wherein the heparin in the wetted heparin is ultra low molecular weight heparin.
11. The solid pharmaceutical composition of claim 1 , wherein the ratio of the delivery agent to the heparin (mg to USP heparin units) in the wetted heparin ranges from about 1:20 to about 1:400.
12. The solid pharmaceutical composition of claim 1 , wherein the delivery agent and wetted heparin are gelled together.
13. The solid pharmaceutical composition of claim 1 , further comprising a gelling agent.
14. The solid pharmaceutical composition of claim 1 , wherein the solid pharmaceutical composition comprises a sufficient amount of delivery agent to cause gelling of the delivery agent and wetted heparin.
15. The solid pharmaceutical composition of claim 1 , wherein the wetted heparin comprises heparin and a wetting agent.
16. The solid pharmaceutical composition of claim 15 , wherein the delivery agent is partially solubilized by the wetting agent.
17. A solid dosage form comprising the solid pharmaceutical composition of claim 1 .
18. The solid dosage form of claim 17 , wherein the solid dosage form is a tablet.
19. The solid dosage form of claim 17 , wherein the solid dosage form is a capsule.
20. The solid dosage form of claim 19 , wherein the solid dosage form is a soft gelatin capsule.
21. The solid dosage form of claim 19 , wherein the solid dosage form is a hard gelatin capsule.
22. The solid pharmaceutical composition of claim 1 , wherein the dosage of heparin is greater than about 150,000 IU.
23. The solid pharmaceutical composition of claim 22 wherein the dosage of heparin is about 15,000 IU to about 150,000 IU.
24. The solid pharmaceutical composition of claim 23 wherein the dosage of heparin is about 25,000 IU to about 90,000 IU.
25. The solid pharmaceutical composition of claim 24 wherein the dosage of heparin is about 30,000 IU to about 80,000 IU.
26. The solid pharmaceutical composition of claim 25 wherein the dosage of heparin is about 37,500 IU to about 75,000 IU.
27. The solid pharmaceutical composition of claim 26 wherein the dosage of heparin is about 37,500 IU.
28. The solid pharmaceutical composition of claim 26 wherein the dosage of heparin is about 40,000 IU.
29. The solid pharmaceutical composition of claim 26 wherein the dosage of heparin is about 50,000 IU.
30. The solid pharmaceutical composition of claim 26 wherein the dosage of heparin is about 60,000 IU.
31. The solid pharmaceutical composition of claim 26 wherein the dosage of heparin is about 75,000 IU.
32. The solid pharmaceutical composition of claim 4 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is less than about 2.4 g.
33. The solid pharmaceutical composition of claim 32 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is less than about 2.2 g.
34. The solid pharmaceutical composition of claim 33 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is less than about 1.8 g.
35. The solid pharmaceutical composition of claim 34 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is less than about 1.2 g.
36. The solid pharmaceutical composition of claim 35 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is less than about 1 g.
37. The solid pharmaceutical composition of claim 36 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is less than about 0.9 g.
38. The solid pharmaceutical composition of claim 37 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is less than about 0.8 g.
39. The solid pharmaceutical composition of claim 38 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is less than about 0.7 g.
40. The solid pharmaceutical composition of claim 39 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is less than about 0.6 g.
41. The solid pharmaceutical composition of claim 40 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is less than or equal to about 0.5 g.
42. The solid pharmaceutical composition of claim 4 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is about 50 mg to about 2.4 g.
43. The solid pharmaceutical composition of claim 42 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is about 100 mg to about 1.2 g.
44. The solid pharmaceutical composition of claim 43 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is about 900 mg to about 1.2 g.
45. The solid pharmaceutical composition of claim 44 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is about 1.15 g.
46. The solid pharmaceutical composition of claim 43 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is about 125 mg to about 1 g.
47. The solid pharmaceutical composition of claim 46 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is about 250 mg to about 750 mg.
48. The solid pharmaceutical composition of claim 47 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is about 400 mg to about 600 mg.
49. The solid pharmaceutical composition of claim 48 wherein the dosage of monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate is about 500 mg.
50. A method for administering heparin to an animal comprising the step of administering the solid pharmaceutical composition or dosage form of claim 1 .
51. A method of treating or preventing thrombosis in an animal comprising orally administering an anti-thrombosis effective amount of the solid pharmaceutical composition or dosage form of claim 1 .
52. The method of claim 51 , wherein the thrombosis is deep vein thrombosis or pulmonary embolism.
53. The method of claim 51 wherein said effective amount is sufficient to increase the activated partial thromboplastin time by at least about 100% as compared to an untreated state of the same subject.
54. The method of claim 53 wherein said effective amount is sufficient to increase the activated partial thromboplastin time by at least about 150% as compared to an untreated state of the same subject.
55. The method of claim 54 wherein said effective amount is sufficient to increase the activated partial thromboplastin time by at least about 165% as compared to an untreated state of the same subject.
56. The method of claim 55 wherein said effective amount is sufficient to increase the activated partial thromboplastin time by at least about 200% as compared to an untreated state of the same subject.
57. The method of claim 51 wherein said effective amount is sufficient to increase the AntiFactor Xa to about 0.05 to about 0.4 IU/ml.
58. The method of claim 57 wherein said effective amount is sufficient to increase the AntiFactor Xa to about 0.15 to about 0.35 IU/ml.
59. The method of claim 58 wherein said effective amount is sufficient to increase the AntiFactor Xa to about 0.15 to about 0.20 IU/ml.
60. The method of claim 59 wherein said effective amount is sufficient to increase the AntiFactor Xa to about 0.2 IU/ml.
61. The method of claim 51 wherein said effective amount is sufficient to increase the AntiFactor Xa to greater than about 0.05 IU/ml.
62. The method of claim 61 wherein said effective amount is sufficient to increase the AntiFactor Xa to greater than about 0.1 IU/ml.
63. The method of claim 62 wherein said effective amount is sufficient to increase the AntiFactor Xa to greater than about 0.15 IU/ml.
64. A method of preparing a solid dosage form of wetted heparin comprising the steps of:
(a) blending a delivery agent and heparin;
(b) adding the delivery agent and heparin to a wetting agent to obtain a composition containing wetted heparin,
wherein the delivery agent is of the formula:
wherein
R 1 , R 2 , R 3 and R 4 are independently hydrogen, —OH, —NR 6 R 7 , halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;
R 5 is a substituted or unsubstituted C 2 -C 16 alkylene, or substituted or unsubstituted C 2 -C 16 alkenylene; and
R 6 and R 7 are independently hydrogen, oxygen, or C 1 -C 4 alkyl.
65. The method of claim 64 , wherein the heparin in the wetted heparin is selected from unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, and mixtures thereof.
66. The method of claim 64 , wherein the heparin in the wetted heparin is unfractionated heparin.
67. The method of claim 64 , wherein the heparin in the wetted heparin is low molecular weight heparin.
68. The solid dosage form of claim 64 , wherein the heparin in the wetted heparin is very low molecular weight heparin.
69. The method of claim 64 , wherein the heparin in the wetted heparin is ultra low molecular weight heparin.
70. A method of improving the bioavailability of a solid heparin dosage form containing unwetted heparin, comprising the step of:
(a) substituting the unwetted heparin in the dosage form with wetted heparin.
71. The method of claim 70 , wherein the heparin in the wetted heparin is selected from unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, and mixtures thereof.
72. The method of claim 70 , wherein the heparin in the wetted heparin is unfractionated heparin.
73. The method of claim 70 , wherein the heparin in the wetted heparin is low molecular weight heparin.
74. The method of claim 70 , wherein the heparin in the wetted heparin is very low molecular weight heparin.
75. The method of claim 70 , wherein the heparin in the wetted heparin is ultra low molecular weight heparin.
76. A method of preventing thrombosis in an animal comprising orally administering an anti-thrombosis effective amount of the solid pharmaceutical composition or dosage form of claim 1 .
77. The method of claim 76 , wherein the thrombosis is deep vein thrombosis or pulmonary embolism.
78. The method of claim 76 wherein said effective amount is sufficient to increase the activated partial thromboplastin time by less than or equal to about 10% as compared to an untreated state of the same patient.
79. The method of claim 78 wherein said effective amount is sufficient to increase the activated partial thromboplastin time by about 10% .
80. The method of claim 79 wherein no or a decreased number of thrombosis is seen as compared to an untreated patient.
81. The method of claim 76 wherein said effective amount is sufficient to increase the activated partial thromboplastin time by more than about 10% as compared to an untreated state of the same patient.
82. The method of claim 76 wherein said effective amount is sufficient to increase the AntiFactor Xa to about 0.05 to about 0.4 IU/ml.
83. The method of claim 82 wherein said effective amount is sufficient to increase the AntiFactor Xa to about 0.15 to about 0.35 IU/ml.
84. The method of claim 83 wherein said effective amount is sufficient to increase the AntiFactor Xa to about 0.25 IU/ml.
85. The method of claim 51 wherein said animal is a mammal.
86. The method of claim 85 wherein said mammal is a human.
87. The method of claim 76 wherein said animal is a mammal.
88. The method of claim 87 wherein said mammal is a human.
89. A method of treating or preventing deep vein thrombosis in a human in need thereof, the method comprising orally administering one or more solid pharmaceutical compositions comprising monosodium N-[8-(2-hydroxybenzoyl)amino] caprylate and wetted heparin, wherein
(1) 120 minutes after oral administration of the solid pharmaceutical composition to a human, the human exhibits one or more of the following:
(i) a plasma activated partial thromboplastin time of at least about 38 seconds,
(ii) an anti-factor IIa plasma concentration of at least about 0.11 IU/ml, or
(iii) an anti-factor Xa plasma concentration of at least about 0.1 IU/ml,
(2) after oral administration of the solid pharmaceutical composition to a human, the human exhibits one or more of the following:
(i) an E max for activated partial thromboplastin time of at least about 50 IU/ml,
(ii) an E AUC(0-inf) for activated partial thromboplastin time of at least 80 IU * hr/ml,
(iii) an E max for anti-factor IIa of at least about 0.35 IU/ml,
(iv) an E AUC(0-inf) for anti-factor IIa of at least about 0.7 IU * hr/ml,
(v) an E max for anti-factor Xa of at least about 0.35 IU/ml,
(vi) an E AUC(0-inf) for anti-factor Xa of at least about 0.68 IU * hr/ml, or
(3) both.
90. The method of claim 89 , wherein the human exhibits a plasma activated partial thromboplastin time of at least about 39 seconds.
91. The method of claim 89 , wherein the human exhibits a plasma activated partial thromboplastin time of at least about 50 seconds.
92. The method of claim 89 , wherein the human exhibits an antifactor IIa plasma concentration of at least about 0.2 IU/ml.
93. The method of claim 89 , wherein the human exhibits an antifactor Xa plasma concentration of at least about 0.2 IU/ml.
94. The method of claim 89 , wherein the human exhibits an E AUC(0-inf) for activated partial thromboplastin time of at least about 100 IU * hr/ml.
95. The method of claim 89 , wherein the human exhibits an E AUC(0-inf) for activated partial thromboplastin time of at least about 150 IU * hr/ml.
96. The method of claim 89 , wherein the human exhibits an E AUC(0-inf) for activated partial thromboplastin time of at least about 180 IU * hr/ml.
97. The method of claim 89 , wherein the human exhibits an E max for anti-factor IIa of at least about 0.4 IU/ml.
98. The method of claim 89 , wherein the human exhibits an E AUC(0-inf) for anti-factor IIa of at least about 1.0 IU * hr/ml.
99. The method of claim 89 , wherein the human exhibits an E max for anti-factor Xa of at least about 0.4 IU/ml.
100. The method of claim 89 , wherein the human exhibits an E AUC(0-inf) for anti-factor Xa of at least about 1.0 IU * hr/ml.
101. The method of claim 89 , wherein the heparin in the wetted heparin is selected from unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, and mixtures thereof.
102. The method of claim 89 , wherein the heparin in the wetted heparin is unfractionated heparin.
103. The method of claim 89 , wherein the heparin in the wetted heparin is low molecular weight heparin.
104. The method of claim 89 , wherein the heparin in the wetted heparin is very low molecular weight heparin.
105. The method of claim 89 , wherein the heparin in the wetted heparin is ultra low molecular weight heparin.Cited by (0)
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